Yellow Fever Vaccine

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Yf-Vax

SIDE EFFECTS

Adverse reactions to 17D yellow fever vaccine include
mild headaches, myalgia, low-grade fevers, or other minor symptoms for 5 to 10
days. Local reactions including edema, hypersensitivity, pain or mass at the
injection site have also been reported following yellow fever vaccine
administration. Immediate hypersensitivity reactions, characterized by rash,
urticaria, and/or asthma, are uncommon and occur principally among persons with
histories of egg allergy.1,2,24

No placebo-controlled trials to assess the safety of
yellow fever 17D vaccines have been performed. However, between 1953 and 1994,
reactogenicity of 17D-204 vaccine was monitored in 10 uncontrolled clinical
trials. The trials included a total of 3,933 adults and 264 infants greater than
4 months old residing in Europe or in yellow fever endemic areas. Self-limited
and mild local reactions consisting of erythema and pain at the injection site
and systemic reactions consisting of headache and/or fever occurred in a
minority of subjects (typically less than 5%) 5 to 7 days after immunization.
In one study involving 115 infants age 4 to 24 months the incidence of fever
was as high as 21%. Also in this study, reactogenicity of the vaccine was
markedly reduced among a subset of subjects who had serological evidence of
previous exposure to yellow fever virus. Only two of the ten studies provided
diary cards for daily reporting; this method resulted in a slightly higher
incidence of local and systemic complaints.1

In 2001, YF-VAX vaccine was used as a control in a
double-blind, randomized comparative trial with another 17D-204 vaccine,
conducted at nine centers in the US. YF-VAX vaccine was administered to 725
adults ≥ 18 years old with a mean age of 38 years. Safety data were
collected by diary card for days 1 through 10 after vaccination and by
interview on days 5, 11, and 31. Among subjects who received YF-VAX vaccine,
there were no serious adverse events, and 71.9% experienced non-serious adverse
events judged to have been related to vaccination. Most of these were injection
site reactions of mild to moderate severity. Four such local reactions were considered
severe. Rash occurred in 3.2% and urticaria in two subjects. Systemic reactions
(headache, myalgia, malaise, and asthenia) were usually mild and occurred in
10% to 30% of subjects during the first few days after vaccination. The
incidence of non-serious adverse reactions, including headache, malaise,
injection site edema, and pain, was significantly lower in subjects > 60
years compared to younger subjects. Adverse events were less frequent in the
1.7% of vaccinated subjects who had pre-existing immunity to yellow fever
virus, compared to those who had not been previously exposed.16

A CDC analysis of data submitted to the Vaccine Adverse
Events Reporting System (VAERS) between 1990 and 1998 suggests that patients
aged 65 or older are at increased risk for systemic adverse events temporally
associated with vaccination, compared to the 25- to 44-year-old age group (see PRECAUTIONS
section, Geriatric Use subsection). The rate of systemic adverse events
occurring post-vaccination in patients age 65 to 74 was 2.5 times higher than
the rate occurring in patients age 25 to 44, based on incidence rates of 6.21
and 2.49 per 100,000 doses of vaccine in the two groups, respectively.38

Neurotropic Disease

Vaccine-associated neurotropic disease2,
previously described as post-vaccinal encephalitis1, is a known rare
serious adverse event associated with 17D vaccination. Age less than 9 months and
immunosuppression are known risk factors. Twenty-one cases of
vaccine-associated neurotropic disease associated with all licensed 17D
vaccines have been reported between 1952 and 2004, 18 in children or
adolescents. Fifteen of these cases occurred prior to 1960, thirteen of which
occurred in infants 4 months of age or younger, and two of which occurred in
infants six and seven months old. Six cases were reported between 1960 and
1996, world-wide. Three occurred in children, including a one-month-old infant,
a three-year-old, and a thirteen-year-old. The three-year-old died of
encephalitis, and a genetic variant of the vaccine virus was isolated from the
brain in this case.39 This is the only verified fatality due to
yellow fever vaccineassociated neurotropic disease. The three remaining cases
of vaccine-associated neurotropic disease since 1960 occurred in adults.1

The incidence of vaccine-associated neurotropic disease
in infants less than 4 months old is estimated to be between 0.5 and 4 per
1,000, based on two historical reports where denominators are available.40,41
No data are available for calculation of an age-specific incidence rate in the
4- to 9-month-age group. A study in Senegal42 described two fatal
cases of encephalitis possibly associated with 17D-204 vaccination among 67,325
children between the ages of 6 months and 2 years, for an incidence rate of 3
per 100,000. One study conducted in Kenya in 1993 detected four cases of encephalitis
temporally associated with vaccination, one in a 2-year-old child and three in
adults, for an incidence of 5.3 cases per million vaccinees of all ages.1

Viscerotropic Disease

Vaccine-associated viscerotropic disease, previously
described as multiple organ system failure26, is a known rare
serious adverse event associated with 17D vaccination. No cause and effect relationship
has been established between vaccination and these subsequent illnesses.
Physicians should therefore be cautious to administer yellow fever vaccine only
to those persons truly at risk of exposure to wild-type yellow fever virus
infection.2

Between 1996 and 1998, four patients, ages 63, 67, 76,
and 79, became severely ill 2 to 5 days after vaccination with YF-VAX vaccine.
Three of these 4 subjects died. The clinical presentations were characterized
by a non-specific febrile syndrome with fatigue, myalgia, and headache, rapidly
progressing to a severe illness including respiratory failure, elevated
hepatocellular enzymes, lymphocytopenia and thrombocytopenia,
hyperbilirubinemia, and renal failure requiring hemodialysis.26 None
of these subjects had vaccine-associated neurotropic disease. In two cases
where vaccine virus was recovered from serum, limited nucleotide sequence
analysis of the viral genome suggested that the isolates had not undergone a
mutation associated with an increase in virulence. The incidence rate for these
serious adverse events was estimated at 1 per 400,000 doses of YF-VAX vaccine,
based on the total number of doses administered in the US civilian population
during the surveillance period.

Vaccine-associated viscerotropic disease temporally
associated with yellow fever vaccination has also been reported in Australia
and Brazil. One Australian citizen became ill after receiving an immunization
with the 17D-204 strain of yellow fever vaccine in his home country,28
and two Brazilian citizens (age 5 and 22 years) became ill three to four days
after receiving 17DD vaccine in Brazil.29 In the Brazilian and
Australian cases, histopathologic changes in the liver included midzonal
necrosis, microvesicular fatty change, and Councilman bodies, which are
characteristic of wild-type yellow fever. Vaccine-type yellow fever virus was
isolated from blood and autopsy material (ie, brain, liver, kidney, spleen,
lung, skeletal muscle, or skin) of each of these three persons, all of whom died
8 to 11 days after vaccination. In Brazil, an estimated 23 million vaccine
doses were administered during the 15-month period during which the two cases
of multiple organ system failure were reported.29

In view of the data cited above, both the 17D-204 and
17DD yellow fever vaccines may be considered as a possible, but rare, cause of
vaccine-associated viscerotropic disease2 that is similar to
fulminant yellow fever caused by wild-type yellow fever virus. All available
evidence from complete nucleotide sequence analysis and testing in experimental
animals of vaccine-type yellow fever viruses isolated from the Brazilian
subjects suggests that the occurrences are due to undefined host factors,
rather than to intrinsic virulence of the 17DD vaccine viruses.27

Because of a lack of tissue specimens from most of the US
cases of vaccine-associated viscerotropic disease and the qualitative
differences between the US cases and those identified in Brazil and Australia,
no definitive support for a causal relationship exists between receipt of YFVAX
vaccine and vaccine-associated viscerotropic disease. However, the temporal
association with recent receipt of yellow fever vaccine and the similarity of
the clinical presentations among all four US cases suggest that the vaccine may
play a role in pathogenesis of the cases.

Pregnancy

Safety of YF-VAX vaccine was evaluated in a study
involving 101 Nigerian women, the majority of whom (88%) were in the third
trimester of pregnancy. In this study, it appeared that vaccinating pregnant
women with the 17D-204 strain of yellow fever vaccine was not associated with
adverse events affecting the mother or fetus. There were no adverse events
among 40 infants who were carefully followed up for one year after birth, and
none of these infants tested positive for IgM antibodies as a criterion for
transplacental infection. However, the percentage of pregnant women who
seroconverted was significantly reduced compared to a non-pregnant control
group (38.6% vs. 81.5%).18

Following a mass immunization campaign in Trinidad,
during which 100 to 200 pregnant females were immunized, no adverse events
related to pregnancy were reported. In addition, 41 cord blood samples were
obtained from infants born to mothers immunized during the first trimester. One
of these infants tested positive for IgM antibodies in cord blood. The infant
appeared normal at delivery and no subsequent adverse sequelae of infection
were reported. However, this result suggests that transplacental infection with
17D vaccine viruses can occur.44

A recent case-control study of spontaneous abortion
following vaccination of Brazilian women found no significant difference in the
odds ratio among vaccinated women compared to a similar unvaccinated group.45

Reporting Of Adverse Events

The US Department of Health and Human Services has
established the Vaccine Adverse Event Reporting System (VAERS) to accept all
reports of suspected adverse events after the administration of any vaccine.
Reporting of all adverse events occurring after vaccine administration is
encouraged from vaccine recipients, parents/guardians and the health care provider.
Adverse events following immunization should be reported to VAERS. Reporting
forms and information about reporting requirements or completion of the form
can be obtained from VAERS through a toll-free number 1-800-822-7967.30
Reporting forms may also be obtained at the FDA web site at
http://vaers.hhs.gov.

In a prospective study, persons given 5 cc of
commercially available immune globulin did not experience alterations in
immunologic responses to the yellow fever vaccine.2,36

The anti-malarial drug chloroquine has been administered
with yellow fever vaccine.2,37

Patients On Corticosteroid Therapy

Oral Prednisone or other systemic corticosteroid therapy
may have an immunosuppressive effect on recipients of yellow fever vaccine that
potentially decreases immunogenicity and increases the risk of adverse events
(see CONTRAINDICATIONS section). Intra-articular, bursal, or tendon injections
with Prednisone or other corticosteroids should not constitute an increased
hazard to recipients of yellow fever vaccine.

Patients With Asymptomatic HIV Infection

Subjects with asymptomaticHIV infection who have had
recent laboratory verification of adequate immune system function and who
cannot avoid potential exposure to yellow fever virus should be offered the
choice of vaccination. Vaccinees should be monitored for possible adverse effects.
The seroconversion rate to 17D vaccines is likely to be reduced in these
patients.17 Therefore, documentation of a protective antibody response
is recommended before travel. (See CLINICAL PHARMACOLOGY section.) For
discussion of this subject and for documentation of the immune response to
vaccine where it is deemed essential, the CDC may be contacted 1970- 221-6400.